Is PGT-A, Preimplantation Genetic Screening (PGS) Really Worth It?
Preimplantation genetic screening (PGS) has been available for IVF patients for over a decade now and allows for the transfer of the best and the most healthy embryos first. However, as with all new technologies, it has as many supporters as opponents. The webinar host is Dr Benjamin Abramov, the Medical Director at GENNET City Fertility who reviews all the information concerning PGS and answers the basic question: is genetic embryo screening really worth it?
Dr Abramov starts with describing the standard routine of IVF treatment. In IVF treatment without PGS, patients very often have a number of embryos they need to make a decision about. They have to decide whether these day-3 or day-5 embryos should be retransplanted. The decision is made on the basis of observational parameters, in other words: how well does the embryo look under the microscope. With PGS however you make that decision on the basis of whether the embryo has got a normal makeup of chromosomes. The morphological grading comes second.
Dr Abramov goes on to clarify the terms PGS and PGT-A. It turns out that PGS and PGT-A refer to the exactly the same thing and the exact same technology. PGT-A stands for pre-implantation genetic testing for aneuploidies. PGS is an acronym for pre-implantation genetic screening. PGT-A is the newer nomenclature but both PGS and PGT-A are used interchangeably.
The doctor then explains the meaning of aneuploidy and euploidy. Aneuploidy refers to an incorrect number of chromosomes, namely if the embryo has an addition or a deletion of the whole chromosome or a part of the chromosome. If the embryo has euploidy, it means that there is the correct and complete number of chromosomes with no deletions or additions of the whole chromosome or a chromosome part.
Chromosomes are tiny packages of DNA. We have a total of 23 chromosomes from our father, 23 chromosomes from our mother – 46 chromosomes in total. We can map the chromosomes to check if we have a normal or abnormal complement of chromosomes. In order for us to understand the importance of the normal number of chromosomes, Dr Abramov describes the best-known aberrations in the number of chromosomes: trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), trisomy 13 (Patau syndrome) and Turner syndrome (an example of chromosome deletion and a female condition). Apart from the fact that all of these syndromes result in serious diseases, physical characteristics and malformations, they also be a cause of miscarriages. They are also often associated with advanced maternal age.
What are the reasons to perform the PGS
At this point the doctor considers why we should perhaps think about performing PGS. In fact, PGS is performed not so much to avoid Edwards, Down or Turner syndrome. It is mostly done to improve the chances that the pregnancy will be successful. According to the doctor, there’s also another advantage that PGS may have. A common thought is that if you transfer two or three embryos (that look good but did not undergo preimplantation genetic screening), you may increase the chances of at least one of them leading to a successful pregnancy. The problem with this approach is if the two embryos that are put back have a normal makeup of chromosomes. You then end up with twin pregnancies or even triplet pregnancies. These are pregnancies are high-risk pregnancies. So another advantage of PGS is making sure that the embryo you put back is a lot more likely to implant and you can put it back by itself without another sibling embryo and reduce the risk of multiple pregnancies.
What are the advantages of PGS?
As Dr Abramov summarises, there are a number of advantages of PGS. Firstly, you improve the pregnancy rate. Once you have an embryo with the normal makeup of chromosomes and you put it back, you can expect a pregnancy rate that is similar to that of a woman who is under the age of 35, regardless of her actual age. Secondly, you check whether the embryos have a normal complement of chromosomes in order to decrease the miscarriage rate or the multiple pregnancy race. In this way, you decrease the time to pregnancy, you shorten the fertility journey and you may also offer the patient a treatment plan which is more cost effective.
Dr Abramov also identifies the most ideal candidates for PGS IVF treatment. PGS is offered to women with advanced maternal age, who are more likely to have abnormal embryos. You could also use PGS in women who have multiple implantation failures or severe miscarriages history and to couples who have severe male factor infertility.
However, what is theoretically right very often does not stand the test of reality. Dr Abramov talks about some evidence and concerns that have been flagged up with the use of PGS. The British regulatory body HFEA has classified PGS as an ‘add-on’. The definition of an add-on is not necessarily the best term to be used: it is an emergent technique or technology that may have shown some promising results in initial studies or may have been around for a number of years, but has not necessarily been proven to improve pregnancy or birth rates.
Dr Abramov explains that we cannot say with 100% confidence that the application of PGS in IVF treatment is certain to be definitely advantageous. The HFEA uses a traffic light system to describe the strength of the evidence to support the use of add-ons. When it comes to PGS, its main disadvantage is that the procedure is in fact, a biopsy. The biopsy on day 3 has been given a red light which means that there is no evidence to say that this add-on is effective. Biopsy on day 5 has been given an amber sign, saying that there is a conflicting body of evidence for this add-on and further research is required.
Will PGS increase a patient’s overall chances?
The doctor highlights a very important argument: PGS will not increase a patient’s overall chances of having a baby. The question is how long will it get you toa point when you transfer this embryo. Without PGS the embryo with the normal number of chromosomes will be the last you transfer. In other words, PGS is essentially an embryo selection tool. However, the doctor admits that it is his practice to offer PGS to patients who have only one to two embryos not as an embryo selection tool but rather as a tool to reduce the impact of unsuccessful pregnancy on their emotional or psychological wellbeing. It will not guarantee a successful pregnancy but it will reduce the risk of ending up with another disheartening event: another miscarriage, another pre-term labour with another diagnosis of chromosomal abnormality.
What are the concerns with PGS?
There are two main concerns with PGS. There is a degree of risk that the biopsy as a procedure may cause damage to the embryos and therefore will reduce the overall chances of conception. You may end up hampering the chances of an embryo to implant although it has a normal complement of chromosomes. This happens because you removed a few cells from the layer of the cells that will become the placenta and the membranes. Another concern is that the cells sampled will not reflect the make-up of chromosomes of the entire embryos but rather represent a limited local area of abnormality. You may therefore end up discarding embryos which could have led to a successful pregnancy.
Another possibility you have to be ready for if you opt for PGS is that the result of the genetic tests might not conclusively identify the embryos as normal. The only thing you will know is that they are mosaic. It is therefore very difficult to ascertain whether you should transfer these embryos or you should refrain from transferring them. Under certain circumstances, when all the other embryos are abnormal and the only thing doctors have is a mosaic embryo, they do transfer such embryos. There are reports of normal pregnancies and babies that are delivered and they appear to be normal, too. Of course, the majority of such embryos will not implant or miscarry. But you cannot rule out a risk that such embryo would implant and end up with delivery of the baby who may be affected by a serious disability. This is another outcome of the PGS use which you should be aware of.
Questions and Answers from the event
My husband has balanced translocation. We did PGS and transferred the normal embryo but twice it failed. First time it didn’t implant and second tine there was no heartbeat. Was there something wrong in PGS result ? Is there any chance to get normal embryo in our case ?
First of all, I’m really sorry to hear this and read it. You normally have high expectations when you transfer a normal embryo. I’m thankful for your question because it is important to emphasise the distinction between PGS and PGD. What you went through is not really PGS. Although the technology is the same, the way the embryos were dealt with, the biopsy and the analysis are exactly the same thing. What you had was the pre-implantation genetic diagnosis. I would call it this way because you have a non-genetic issue. A non-genetic issue is the fact that your husband is a carrier of a balanced translocation. Having a balanced chromosome translocation doesn’t affect you because you still have a normal copy of all the genes that you need. The issue with having a balanced chromosome translocation is that the embryos that you produce will be a mix of normal embryos and abnormal embryos. But the vast majority of the embryos that you produce will be abnormal, regardless of female age. And because the vast majority of the embryos that you produce are abnormal, you are lot more prone to the failure of implantation and a lot more prone to miscarriages. So in my opinion, there is no doubt that in your case the biopsy and the chromosome analysis of your embryos is essential. Because without it, you subject yourself to the risk of miscarriages and a long period of time before you happen to have a normal embryo implant naturally. Now why your embryos did not implant and why, when it implanted, it did not go any longer than a certain stage and you had no heartbeat, that is a very difficult question to answer. Is it related to the fact that you had a biopsy on those embryos? Perhaps. As I said, there is a degree of concern as to what the biopsy causes to the embryos. At the end of the day, you remove a few cells from the layer of cells that needs to become the placenta and membranes. So you could perhaps hamper the implantation process and the formation of the placenta. But in your case it is important to look at other possible causes, the ones that have perhaps to do with what is happening with you. Do you have any uterine malformations? Do you have any circulating antibodies that cause an antiphospholipid syndrome?Do you have any issues with your clotting system? This is what your doctors and fertility experts should determine. I hoped that it answered your question.
Is PGS always safe for a blastocyst or must an embryologist be very experienced to perform this procedure?
Again a brilliant question, thank you for that. You need to have your biopsy by an experienced practitioner. There is a recent study that showed that there is a significant difference in the outcome according to the experience of the practitioner. If the practitioner is really skilful, he or she will remove just about what you need for the sake of the chromosome analysis, 4, 5 or 6 cells. If the practitioner is not that experienced, he or she will remove 10 cells or so. That will have much more pronounced effect on the health of your embryos. If you go to the other extreme and you remove fewer cells than you ought to, you have failure of the amplification of the genetic material and you have inconclusive results. So the answer to your question is: you certainly need to have your biopsy carried out in the centre that has good practitioners.
Is PGS indicated for IVF with egg donation, especially if the donor age is less than 30?
This is a good question because it illustrates the dilemmas in our field. If your donor is younger than 30 years old, chances are that the vast majority of embryos she produces are chromosomally normed. At the age of 31 or 32, the rate of abnormalities is estimated to be at around 30%. So there is a good chance that the embryos you are transferring are actually chromosomally abnormal. So you need to balance here the odds with the possibility that the biopsy will do more harm than good. And the question there is how many embryos do you have? And how many attempts have you had so far? So if it the first embryo transfer and if you have four blastocysts, my inclination would be just put the blastocysts back, do not inflict any possible damage on them by doing the biopsy and you will have the good chance that what you’re putting back is chromosomally genetically normal. But if you have had 2 failed cycles with the same donor, and you have another 6 or 8 blastocysts in the storage, then you might be starting to think ‘How many more embryo transfers am I going to do before I get the understanding whether the failures are to do with abnormal makeup of chromosomes or due to a different story?’ Well, the answer to your question is: ‘It really depends on your circumstances.’ I hope it answered your question but if not, then I will be happy to elaborate.
We have transferred NGS tested normal embryo. However, it resulted as biochemical pregnancy. The explanation from our MD was that the embryo didn’t have enough energy. Do you think that it’s embryo related? Prior to the transfer, we have done ERA, uterus biopsy for NK cells and hysteroscopy just to ensure that our embryo will implant. Now we have done another cycle before moving to DE. We have 6 day3 embryos frozen from this cycle, we will make them to proceed to day5 and then transfer as a blast without NGS this time
Biochemical pregnancies are a difficult issue in our field. I have to be honest and tell you that we don’t completely understand why biochemical pregnancies happen. I think what your practitioner eluded to when he or she said that the embryo did not have enough energy was along the lines of the analysis of the mitochondria in the embryos and the eggs. Mitochondria are little structures that are found in any cell, they are the power plants of the cell. They produce the energy that the cell needs to maintain its processes and infrastructure. There is an observation that shows that eggs of older women have got fewer mitochondria. There is a theory that suggests that embryos can implant or fail to implant not only because they have a normal makeup of chromosomes or they have an abnormal makeup of chromosomes. You can test that when you do PGS. The issue there is that you can think about IVF as having your embryos put through a sieve. The first sieve is the morphology or the development in the lab. You have embryos that make it to day 3 and fail to make it to day 5. That’s the first sieve. And then you have a number of day 5 embryos blastocysts and then you can do a biopsy on them and see whether they have a normal makeup of chromosomes or they don’t. And as you could have learned in between the lines of my talk, you got to be lucky to be able to have one or two or three normal embryos, with the normal makeup of chromosomes that you can transfer. Now if you add another sieve, then you can have fewer embryos that are suitable to transfer. I am not sure to what extent the mitochondrial analysis of the embryos is a useful clinical tool. That’s the answer to my question. But it could be that the embryo that you put back did not implant because of that issue. It did not go beyond implantation because of the fact that it had biopsy. It could have to do with completely other factors. It would be very difficult to post a finger on a single factor and tell you that this is what might have caused it.
I think your decision is sensible. If you have 6 day 3 embryos, you need to see how it turns out and develops. It’s normally the case although sometimes we are really lucky and the outcome is really good. It’s normally the case that not all day 3 embryos become blastocysts. So you may end up with fewer than six blastocysts. And if you have two, three blastocysts, it is possibly the case that the better way of going about it is just to transfer.
Going back again to my question regarding the balanced translocation, is our only hope to use donor sperm then?
No, absolutely not. The odds are that the vast majority of your embryos carry an abnormality. But you still make normal embryos. The ratio between the normal embryos and the abnormal embryos is unfavourable but you do still have a chance of ending up with a normal embryo. So it is really a question of resilience. I do not know where you are having your treatment but here in the UK a lot of what we do is self-funded. So there is the issue of financial resources. There is obviously the issue of emotional resources. This is emotionally taxing, it is difficult to go to a treatment. It is difficult to go through the phase that you wait for the biopsy results and then you put the embryo back and you wait for the result of the pregnancy test. Then you wait for the scan to see if there’s metal heartbeat. So this is mainly the question of how resilient you are: financially, psychologically, emotionally. But you do still have a chance of having a normal embryo found in this process and you do have a chance that this normal embryo will implant and end up with a healthy baby. I can tell you from my experience that I have treated lots of patients with balanced chromosomal translocation and in many of them we were successful. It’s a question of how many times you’re happy to try this.
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